Association between urinary uric acid excretion and kidney outcome in patients with CKD

Inhibiting tubular urate reabsorption may protect the kidney from urate-induced tubular injury. However, this approach may promote intratubular uric acid crystallization, especially in acidified urine, which could be toxic to the kidney. To assess how tubular urate handling affects kidney outcomes, we conducted a retrospective cohort study including 1042 patients with estimated glomerular filtration rates (eGFR) of 15–60 mL/min/1.73 m2. The exposures were fractional excretion of uric acid (FEUA) and urinary uric acid-to-creatinine ratio (UUCR). The kidney outcome was defined as a halving of eGFR from baseline or initiating kidney replacement therapy. The median FEUA and UUCR were 7.2% and 0.33 g/gCre, respectively. During a median follow-up of 1.9 years, 314 kidney outcomes occurred. In a multivariate Cox model, the lowest FEUA quartile exhibited a 1.68-fold higher rate of kidney outcome than the highest FEUA quartile (95% confidence interval, 1.13–2.50; P = 0.01). Similarly, lower UUCR was associated with a higher rate of kidney outcome. Notably, patients in the highest quartile of FEUA and UUCR were at the lowest risk of kidney outcome even among those with aciduria. In conclusion, lower FEUA and UUCR were associated with a higher risk of kidney failure, suggesting that increased urate reabsorption is harmful to the kidney.


Supplementary Figures
Comparison of baseline characteristics between those with and without data on FEUA Table S2.Baseline characteristics according to UUCR quartile Table S3.Competing-risk regression models for the association of FEUA and UUCR with kidney outcome Table S4.Sensitivity analyses Table S5.Baseline characteristics according to UUA quartile Table S6.Additional analysis for an association between UUA and kidney outcome

Marginal structural model (MSM)
Conceptually, the MSM creates a "pseudo-population" based on inverse probability weights, where there is no association between time-dependent confounders and exposures.In the current study, we compared the risk of outcomes if all patients were continuously exposed to low FEUA (or low UUCR) with the risk of the outcome if they were never exposed to low FEUA (or low UUCR).Inverse probability weights, which are the product of the inverse probability of treatment weights and the inverse probability of censoring weights, were calculated at each 3-month follow-up period.
Inverse probability of treatment weights was the reciprocal of the predicted probability of each patient having their own exposure history.This probability was estimated by fitting logistic regression models conditional on both baseline and time-dependent covariates.Similarly, inverse probability of censoring weights was the reciprocal of the probability of being uncensored as estimated by logistic regression models conditional on both baseline and time-dependent covariates.Inverse probability of treatment weights and inverse probability of censoring weights were stabilized by multiplying them by the predicted probabilities estimated by logistic regression models conditional on baseline covariates only.Inverse probability weights were truncated at the 1st and 99th percentiles.

Figure S1 .
Figure S1.Flow diagram of the study participants

Figure S2 .
Figure S2.Subgroup analyses stratified by the presence or absence of aciduria

Table S1 . Comparison of baseline characteristics between those with and without data on FEUA
Data presented as mean (standard deviation), median [interquartile range], or percent.Abbreviations: FEUA, fractional excretion of uric acid; eGFR, estimated glomerular filtration rate; UPCR, urinary protein-to-creatinine ratio

Table S3 . Competing-risk regression models for the association of FEUA and UUCR with kidney outcome
Models are adjusted for age, sex, body mass index, systolic blood pressure, diabetes mellitus, cardiovascular comorbidities, albumin, estimated glomerular filtration rate, hemoglobin, potassium, phosphate, serum urate, C-reactive protein, urinary protein-to-creatinine ratio, loop and thiazide diuretics, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and xanthine oxidase inhibitors.Abbreviations: FEUA, fractional excretion of uric acid; UUCR, urinary uric acid-to-creatinine ratio; CI, confidence interval